The present invention relates to bis-benzo cyclohepta piperidine, piperidylidene and piperazine compounds and to pharmaceutical compositions and methods of using such compounds.
U.S. Pat. Nos. 3,326,924, 3,717,647 and 4,282,233, European published Application No. 0042544, Villani et al., Journal of Medicinal Chemistry, Vol. 15, No. 7, pp 750-754 (1972) and Arzn. Forsh 36 1311-1314 (1986) describe certain 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines as antihistamines. U.S. Pat. No. 4,355,036 describes certain N-substituted piperidylidene compounds.
WO 88/03138 discloses compounds of the formula ##STR2## or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR.sup.9 where R.sup.9 is O, --CH.sub.3 or --(CH.sub.2).sub.n CO.sub.2 H where n is 1 to 3, and the remaining a, b, c and d groups are CH, which remaining a, b, c and d groups optionally may be substituted with R.sup.1 or R.sup.2 ;
R.sup.1 and R.sup.2 may be the same or different and each independently represents halo, --CF.sub.3, --OR.sup.10, --COR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.11, alkynyl, alkenyl or alkyl, which alkyl or alkenyl group may be substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10 ; PA1 R.sup.3 and R.sup.4 may be the same or different and each independently represents H, any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 together may represent a saturated or unsaturated fused C.sub.5 -C.sub.7 ring; PA1 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represent H, --CF.sub.3, alkyl or aryl, which alkyl or aryl may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2 R.sup.11, --CO.sub.2 R.sup.10, --OPO.sub.3 R.sup.10 or one of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 may be taken in combination with R as defined below to represent --(CH.sub.2).sub.r -- where r is 1 to 4 which may be substituted with lower alkyl, lower alkoxy, --CF.sub.3 or aryl; PA1 R.sup.10 represents H, alkyl or aryl; PA1 R.sup.11 represents alkyl or aryl; PA1 X represents ##STR3## which C may contain an optional double bond to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent H, --R.sup.10, --OR.sup.11 or --OC(O)R.sup.10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent: PA1 H.sub.2 and --(OR.sup.10).sub.2 ; PA1 alkyl and H; PA1 (alkyl).sub.2 ; PA1 --H, and OC(O)R.sup.10 ; PA1 --H and --OR.sup.10 ; PA1 .dbd.O PA1 aryl and H; or PA1 .dbd.NOR.sup.10 and --O--(CH.sub.2).sub.p --O--; PA1 Z represents O, S or H.sub.2 such that PA1 (a) when Z is O, R may be taken in combination with R.sup.5, R.sup.6, R.sup.7 or R.sup.8 as defined above, or R represents H, aryl, alkyl, --SR.sup.11, --N(R.sup.10).sub.2, cycloalkyl, alkenyl, alkynyl or --D wherein --D represents heterocycloalkyl, ##STR4## wherein R.sup.3 and R.sup.4 are as previously defined and W is O, S or NR.sup.10 wherein R.sup.10 is as defined above, PA1 said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substituted with from 1-3 groups selected from --halo, --CON(R.sup.10) --aryl, --CO.sub.2 R.sup.10, --OR.sup.12, --SR.sup.12, --N(R.sup.10).sub.2, --N(R.sup.10)COR.sup.10, --COR.sup.12, --NO.sub.2 or --D, wherein --D and R.sup.10 are as defined above and R.sup.12 represents R.sup.10, --(CH.sub.2).sub.m OR.sup.10 or --(CH.sub.2).sub.q COR.sup.10 wherein R.sup.10 is as previously defined, m is 1 to 4 and q is 0 to 4, PA1 said alkenyl and alkynyl R groups not containing --OH, --SH or --N(R.sup.10).sub.2 on a carbon containing a double or triple bond respectively PA1 (b) when Z represents S, R represents in addition to those alkanediyl R groups above, aryloxy or alkoxy; and PA1 (c) when Z represents H.sub.2, R represents --COOR.sup.10, --E--COOR.sup.10 or --E--OR.sup.12 where E is alkanediyl which may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2 or --D where D, R.sup.10 and R.sup.12 are as previously defined. These compounds are disclosed as being useful in the treatment of allergy and inflammation. PA1 Z represents O or S; PA1 Y represents --(C(R.sup.a).sub.2).sub.m --X--(C(R.sup.a).sub.2).sub.n -- or ##STR6## m and n are integers 0, 1, 2 or 3 such that the sum of m plus n equals 0 to 3; PA1 when m plus n equals 1, X represents --O--, --S(O).sub.e -- where e is 0, 1 or 2, --NR.sup.14 --, --C(O)NR.sup.14 --, --NR.sup.14 C(O)--, --C(S)NR.sup.14 --, --NR.sup.14 C(S)--, --CO.sub.2 -- or --O.sub.2 C--, where R.sup.14 is as defined below; PA1 when m plus n equals 2, X represents --O--, --S(O).sub.e -- where e is 0, 1 or 2, or --NR.sup.14 ; PA1 when m plus n equals 3, then X equals a direct bond PA1 when m plus n equals 0, X can be any substituent as defined for m plus n equalling 1 and X can also be a direct bond, cyclopropylene or propenylene PA1 each R.sup.a may be the same or different and each independently represents H, or C.sub.1 -C.sub.6 lower alkyl; PA1 the dotted line between the indicated carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B each independently represent --R.sup.11, --OR.sup.13, --halo or --OC(O)R.sup.11, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.13).sub.2, (alkyl and H), (alkyl).sub.2, (--H and --OC(O)R.sup.11), (H and --OR.sup.11), .dbd.O or .dbd.NOR.sup.14 ; PA1 R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may be the same or different and each independently represents --H, --halo, --CF.sub.3, --OR.sup.11, --C(.dbd.O)R.sup.11, SR.sup.11, --S(O).sub.e R.sup.13 where e is 1 or 2, --N(R.sup.11).sub.2, --NO.sub.2, --OC(.dbd.O)R.sup.11, --CO.sub.2 R.sup.11, --OCO.sub.2 R.sup.13, NR.sup.11C(.dbd.O)R.sup.11, --CN, --CON(R.sup.11).sub.2, --alkyl, --aryl, --alkenyl or --alkynyl, which alkyl group may be substituted with --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2 or --CO.sub.2 R.sup.11 and which alkenyl group may be substituted with halo, --OR.sup.13 or --CO.sub.2 R.sup.11 ; PA1 in addition, R.sup.1 and R.sup.2 may together form a benzene ring fused to the ring t and/or R.sup.3 and R.sup.4 may together form a benzene ring fused to the ring s; PA1 R.sup.5 and R.sup.6 each independently represents H, alkyl or aryl, which alkyl may be substituted with --OR.sup.11, --SR.sup.11 or --N(R.sup.11).sub.2 ; PA1 in addition, R.sup.5 may be combined with R.sup.6 to represent .dbd.O or .dbd.S; PA1 R.sup.7, R.sup.8 and R.sup.9 each independently represents H, halo, --CF.sub.3, --OR.sup.11, --C(O)R.sup.11, SR.sup.11, --S(O).sub.e R.sup.13 where e is 1 or 2, --N(R.sup.11).sub.2. --NO.sub.2, --CO.sub.2 R.sup.11, --OCO.sub.2 R.sup.13, OCOR.sup.11, --CN, --CON(R.sup.11).sub.2, --NR.sup.11 COR.sup.11, alkyl, awl, alkenyl or alkynyl, which alkyl group may be substituted with --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2, or --CO.sub.2 R.sup.11 and which alkenyl group may be substituted with halo, --OR.sup.13 or --CO.sub.2 R.sup.11 ; PA1 each R.sup.11 independently represents H, alkyl or aryl; PA1 each R.sup.13 independently represents alkyl or aryl; PA1 each R.sup.14 independently represents H or alkyl; PA1 T represents ##STR7## with the dotted line attached to T representing a double bond when T is ##STR8## and being absent when T is ##STR9## PA1 the dotted line represents an optional double bond; PA1 Z represents O or S; PA1 Y represents --CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --, --X--, --CH.sub.2 --X--, --X--CH.sub.2 -- or --(CH.sub.2).sub.3 --, wherein X represents --O--, --S-- or --NR.sup.14 --; PA1 R.sup.1, R.sup.3 and R.sup.9 may be the same or different and each independently represents H, halo, --CF.sub.3, --OR.sup.11, --N(R.sup.11).sub.2, --alkyl, --alkenyl or --alkynyl; R.sup.9 may also be --SR.sup.11 ; PA1 T represents ##STR11## with the dotted line attached to T representing a double bond when T is ##STR12## and being absent when T is
where p is 2, 3 or 4 and R.sup.10 is as previously defined;